Chronic alcohol consumption is associated with increased incidence of certain infections (including tuberculosis), autoimmune diseases, and certain malignancies. Studies aimed at understanding the underlying mechanisms of this apparent adverse modulation of the immune system have found abnormalities in both innate and adaptive immunity. Immunological studies in humans have been hampered by the lack of longitudinal studies and by the complicating factors introduced by alcoholic liver disease. Animal models of chronic ethanol (ETOH) ingestion can afford the luxury of examining the effect of the dose and duration of ETOH ingestion on various immune functions. A safe and effective protocol for chronic ETOH administration in mice has been recently developed and will be utilized in this application. Recent developments have highlighted the importance of innate immunity not only in early defenses but also in the regulation of the type and magnitude of adaptive immune responses. Natural killer (NK) and NKT cells, major components of innate immunity, influence downstream immune responses both by their cytotoxic activity as well as by their ability to elaborate cytokines. Based on preliminary data, the hypothesis of this application is that ETOH has a biphasic effect on NK cell responses with an early inhibition followed by enhanced activities. In contrast, it appears ETOH has a persistent inhibitory effect on NKT cells. The net effect of ethanol on these activities may be due to a combination of a direct effect on the cells themselves as well as indirect effects known to modulate their activity such as Class I MHC expression, prostaglandin synthesis, cytokines, cytokine receptors, and dendritic cells (DC). These mechanisms, and their in vivo relevance, will be examined. Preliminary data indicate that the effect of ETOH on innate immunity extends beyond its effect on the baseline activity. Mycobacterial DNA and DNA fragments are potent immunostimulatory agents and were the influence for the development of CpG oligodeoxynucleotides (ODN). Since mycobacterial infections are seen in a high incidence rate in alcoholics, one hypothesis is that ETOH blunts the response to mycobacterial DNA. Preliminary data prompted the hypothesis that ETOH blunts the enhanced NK activity induced by CpG ODN [unreadable] [unreadable]